Approximately 30,000 people in the United States are diagnosed each year with pancreatic Cancer (PanCa). Over 90% of these will die of the disease making PanCa one of the most devastating human malignancies. The current 5-year survival rate of less than 4% has changed little in the last 20 years despite improvements in therapy including the introduction of chemotherapeutic agents such as gemcitabine (gemzar). Thus, there is an urgent need for an improved therapy for the 80% of PanCa that are unresectable and/or metastatic. Progress has been made toward delineating the genetic errors contributing to PanCa thus opening up new approaches to therapy. The HER-2 proto-oncogene is overexpressed in 60-80% of PanCa. Down modulation of HER-2 protein via the antisense (AS) approach can inhibit PanCa cell growth in vitro and in vivo. However, until now efficient systemic AS oligonucleotide (ODN) delivery has been problematic. We have developed a tumor-targeted liposomal AS ODN complex using an anti-transferrin receptor single-chain antibody fragment (TfRscFv) as the targeting entity. This immunoliposome complex can systemically deliver AS HER-2 (ODN) preferentially to PanCa tumors regardless of their HER-2 levels. In preliminary experiments, the resultant down modulation of HER-2 leads to an increased sensitization of PanCa tumor cells to gemzar. In this Phase I proposal of a Fast-Track application we propose to optimize the TfRscFvliposome- AS HER-2 complex for PanCa cells. This optimization will result not only in high transfection efficiency in vitro, but also in tumor specific targeting in vivo after systemic delivery. This will be confirmed using both subcutaneous xenograft and orthotopic metastases mouse models. We will also continue to develop a lyophilized form of the complex with increased shelf life. Our ultimate goal is to develop this systemic, tumor-targeting immunoliposome AS HER-2 complex for use in combination with gemzar as a novel and effective treatment modality for PanCa. This dual, molecular- and tumor-targeting design has the potential to significantly expand the therapeutic utility of the anti-HER-2 strategy.